Characterization of cell-surface prion protein relative to its recombinant analogue: insights from molecular dynamics simulations of diglycosylated, membrane-bound human prion protein.
Characterization of cell-surface prion protein relative to its recombinant analogue: insights from molecular dynamics simulations of diglycosylated, membrane-bound human prion protein.
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DOI：
10.1111/j.1471-4159.2009.05892.x
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发表时间：
2009-04
影响因子：
4.7
通讯作者：
Daggett V
中科院分区：
文献类型：
--
作者：
DeMarco ML;Daggett V
朊病毒蛋白通过从正常亚型转化为与疾病相关的亚型而导致多种致命的神经退行性疾病。通常研究蛋白质的重组形式以研究转化过程。该构建体缺乏体内存在的共翻译修饰和翻译后修饰，该蛋白质具有两个 N 连接聚糖，并通过糖基磷脂酰肌醇 (GPI) 锚结合到质膜的外层。聚糖固有的灵活性和异质性、GPI 锚的可塑性以及蛋白质在膜中的定位，共同使得 PrPC 生物构建体的实验结构表征具有挑战性。然而，这种表征不仅对于确定重组 PrPC 作为蛋白质生物形式模型的适用性至关重要，而且对于确定共翻译和翻译后修饰对疾病过程的潜在作用至关重要。在这里，我们提出了三种人类 PrP 构建体的分子动力学模拟：（1）模拟重组形式的纯蛋白质构建体，（2）二糖基化和可溶性构建体，以及（3）与脂质双层结合的二糖基化和 GPI 锚定构建体。我们发现糖基化和膜锚定不会显着改变 PrPC 的结构或动力学，但它们确实明显改变了多肽表面 PrPC 的可及性。此外，膜结合 PrPC 的模拟揭示了疾病引发 PrPC:PrPSc 结合事件的可能识别域，以及观察到的与差异糖基化 PrP 种类相关的转化低效的潜在机制。
The prion protein is responsible for several fatal neurodegenerative diseases via conversion from its normal to disease-related isoform. The recombinant form of the protein is typically studied to investigate the conversion process. This constructs lacks the co- and post-translational modifications present in vivo, there the protein has two N-linked glycans and is bound to the outer leaflet of the plasma membrane via a glycosylphosphatidylinositol (GPI) anchor. The inherent flexibility and heterogeneity of the glycans, the plasticity of the GPI anchor and the localization of the protein in a membrane conspire to make experimental structural characterization of biological constructs of PrPC challenging. Yet this characterization is central to determining not only the suitability of recombinant PrPC as a model for biological forms of the protein but also the potential role of co- and post-translational modifications on the disease process. Here, we present molecular dynamics simulations of three human PrP constructs: (1) a protein-only construct modeling the recombinant form, (2) a diglycosylated and soluble construct, and (3) a diglycosylated and GPI-anchored construct bound to a lipid bilayer. We found that glycosylation and membrane anchoring do not significantly alter the structure or dynamics of PrPC, but they do appreciably modify the accessibility of the polypeptide surface PrPC. Additionally, the simulations of membrane-bound PrPC revealed likely recognition domains for the disease-initiating PrPC:PrPSc binding event and a potential mechanism for the observed inefficiency of conversion associated with differentially glycosylated PrP species.
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影响因子：
2.9
作者：
DeMarco, Mari L.;Silveira, Jay;Daggett, Valerie
通讯作者：
Daggett, Valerie
影响因子：
3.9
作者：
FERGUSON, MAJ;HOMANS, SW;RADEMACHER, TW
通讯作者：
RADEMACHER, TW
影响因子：
4.8
作者：
Eberl, H;Tittmann, P;Glockshuber, R
通讯作者：
Glockshuber, R
影响因子：
--
作者：
Ceroni A;Dell A;Haslam SM
通讯作者：
Haslam SM
影响因子：
16.2
作者：
DeArmond, SJ;Sánchez, H;Prusiner, SB
通讯作者：
Prusiner, SB